Peripheral nerve remodeling in the tumor microenvironment: neuro-immune crosstalk, molecular mechanisms, and...

As a crucial component of the tumor microenvironment, the nervous system modulates tumor initiation, progression, and metastasis. Conversely, tumors actively hijack and reshape neural structures to activate nerve-dependent developmental and regenerative processes that promote their own growth and survival. Despite extensive progress in tumor-neural crosstalk, the molecular mechanisms underlying neuro-immune coordination in peripheral nerve remodeling remain incompletely understood, and integrated strategies targeting this axis to overcome immunotherapy resistance are still lacking. This review comprehensively examines the phenotypic and functional remodeling of the peripheral nervous system within the tumor microenvironment, with a focus on neuro-immune crosstalk between neural cells, immune cells and cancer cells. We systematically analyze phenotypic remodeling in neurons and glial cells, with particular emphasis on autonomic nerve differentiation, functional reprogramming of the neurotrophin family, and the regulatory roles of immune cells in these processes. Finally, we discuss precision therapeutic strategies including β-adrenergic blockades, neurotrophin signaling inhibition, surgical and pharmacological denervation, and combinatorial regimens with immunotherapy, highlighting their translational potential in cancer treatment. Neuro-immune crosstalk in the tumor microenvironment: schematic of four core interaction nodes: This schematic illustrates the bidirectional interactions between peripheral nerves and immune cells within the tumor microenvironment. Schwann cells engage in antigen presentation and cytokine signaling with tumor-associated macrophages and lymphocytes. Sympathetic-derived norepinephrine drives T cell exhaustion and myeloid-derived suppressor cell expansion, while parasympathetic-derived acetylcholine activates α7 nicotinic acetylcholine receptors on immune cells to suppress NF-κB signaling. Macrophage- and lymphocyte-derived NGF and BDNF establish positive feedforward loops that amplify tumor-neural-immune interactions. Together, these interconnected mechanisms support tumor innervation, progression and immune evasion, positioning the neuro-immune axis as an emerging therapeutic target for cancer treatment.